U.S. Pat. No. 4,038,222, issued July 26, 1977 and subsequently reissued as U.S. Pat. No. Re. 29,842 on Nov. 21, 1978 describes the isolation, characterization, synthesis and pharmacological activity of human, porcine and ovine .beta.-endorphin.
U.S. Pat. No. 4,116,950, issued Sept. 26, 1978 describes a series of human .beta.-endorphin analogs which are modified in the carboxyl terminus region with phenylalanine in position 27 and glycine in position 31 and optionally with further substitutions in the amine terminus region such as D-threonine in position 2, or norleucine in position 5 or alanine in positions 6 and 7.
Of all the opioid peptides that correspond to a portion of the structure of .beta.-lipotropin only the structure corresponding to positions 61-91, namely .beta.-endorphin (.beta.-Ep), has shown potent analgesic activity by the intravenous route. Recent studies with synthetic analogs indicate that the complete primary structure of .beta.-endorphin is required for full analgesic activity. See Li et al., Biochem. Biophys. Res. Commun. 85, 795 (1978). Although modifications of the pentapeptide met-enkephalin, representing positions 1 to 5 of .beta.-endorphin, can lead to products with potencies comparable to or even greater than that of .beta.-endorphin, efforts to make the same modifications in positions 1 to 5 of .beta.-encorphin have not led to analogs with increased potencies. Thus far the only analog of .beta.-endorphin that has exhibited greater analgesic activity than the parent is [Phe.sup.27, Gly.sup.31 ]-.beta..sub.h -EP whose potency is about 1.48 times that of the parent by the intravenous assay route. Note U.S. Pat. No. 4,116,950 above. It has now been found that modifications in position 31 and extension at this terminus can unexpectedly lead to compounds exhibiting greater biological potencies.